Evaluation of In-Batch and In-Flow Synthetic Strategies towards the Stereoselective Synthesis of a Fluorinated Analogue of Retro-Thiorphan

A stereoselective synthetic strategy for the preparation of trifluoromethylamine mimics of retro-thiorphan, involving a diastereoselective, metal-free catalytic step, has been studied in batch and afforded the target molecule in good yields and high diastereoselectivity. A crucial point of the synthetic sequence was the catalytic reduction of a fluorinated enamine with trichlorosilane as reducing agent in the presence of a chiral Lewis base. The absolute configuration of the key intermediate was unambiguously assigned by X-ray analysis. The synthesis was also investigated exploiting continuous flow reactions; that is, an advanced intermediate of the target molecule was synthesized in only two in-flow synthetic modules, avoiding isolation and purifications of intermediates, leading to the isolation of the target chiral fluorinated amine in up to an 87:13 diastereoisomeric ratio.


In batch synthesis of the target molecule
Synthesis of (S)-tert-butyl (1-hydroxy-3-phenylpropan-2-yl)carbamate 2 2 A solution of tert-butyl dicarbonate (1eq, 6.7mmol) in DCM (14 mL) was added dropwise to a solution of (S)-2-amino-3-phenylpropan-1-ol (1) (1eq, 6.7mmol) in a mixture of DCM (14 mL) and 1N NaOH (11 mL). The reaction mixture was then stirred at room temperature for 24 h, and the organic phase was separated. The aqueous layer was extracted with DCM (10 mL x 2). The combined organic layers were washed with water (10 mL x 1) and dried over Na2SO4. The solvent was evaporated in vacuo, to afford (S)-tert-butyl (1-hydroxy-3-phenylpropan-2-yl)carbamate (2) as a white solid; the crude has been used without further purification in the following synthetic cascade. All analytical data are in agreement with literature.
Synthesis of (S)-tert-butyl (1-(allyloxy)-3-phenylpropan-2-yl)carbamate 2 3 A solution of (S)-tert-butyl (1-hydroxy-3-phenylpropan-2-yl)carbamate (2) (1 eq, 6.7mmol), 4eq of allylbromide and DMF (0.1 M) was prepared in a flask and stirred under ice bath for 15 min. 1.1eq of KO-tBu were added to the solution portion wise. The thus obtained mixture was stirred for 4h at 0°C and S4 for 12h at r.t. The mixture was diluted with EtOAc and treated with HCl 10%, then the organic phase was treated with NaHCO3 (ss), and finally washed with brine. The organic phases were reunited, dried over Na2SO4, filtered, and then concentrated under vacuum at high temperature to give a crude colourless oil which was used without further purification in the following synthetic step.
All analytical data are in agreement with literature.

S7
Synthesis of Ethyl 3-(((S)-1-(allyloxy)-3-phenylpropan-2-yl)amino)-4,4,4-trifluorobutanoate 6 Dry DMF or the appropriate catalytic chiral Lewis Base in the reported amount (Table 1), and a 0.1 M solution of enamine 5 (1 eq.) in dry CH2Cl2 were introduced in a round bottomed flask under nitrogen atmosphere. The mixture was cooled down to the indicated temperature and HSiCl3 (3.5 eq.) was added to the reaction mixture. After the desired time, the reaction was quenched with a 4 M solution of NaOH until basic pH was reached. The resulting mixture was extracted with CH2Cl2, separated, and the organic phase dried over anhydrous Na2SO4. The solvent was removed under reduced pressure. The residue was purified by column chromatography (silica gel, hexanes/EtOAc = 98:2) to afford 6 as a colorless oil. In order to perform X-ray analysis, a sample of compound 6 was treated with an equimolar amount of HCl in Et2O. The product was slowly crystallized from a mixture of Et2O/hexane to afford light-yellow crystals of 6/HCl. Absolute configuration was determined to be (S,S).
A summary of the experimental details concerning the single-crystal X-ray diffraction study of 6/HCl is reported in Table S1. X-ray data were collected on a Bruker Smart Apex CCD area detector equipped with fine-focus sealed tube operating at 50 kV and 30 mA, using graphite-monochromated Mo Kα radiation (λ = 0.71073 Å). Data reduction was made using SAINT programs; 3 absorption corrections based on multiscan were obtained by SADABS. 3 The structures were solved by SHELXS-97 4 and refined on F2 by full-matrix least-squares using SHELXL-14. 5 The program ORTEP-III 6 was used for molecular graphics.  Synthesis of ethyl 4,4,4-trifluoro-3-(((S)-1-hydroxy-3-phenylpropan-2-yl)amino)butanoate 7 Compound 6 (0.13 mmol, 1 equiv.) in EtOH (1.5 mL) was introduced in a two necks round-bottomed flask equipped with a condenser under N2 atmosphere. Pd(OAc)2 (0.03 mmol, 0.2 equiv.) and PPh3 (0.11 mmol, 0.88 equiv.) in EtOH (1.5 mL) were added to the solution, followed by 300 mg of SiO2. The reaction mixture was stirred at reflux for 20 h. After completion of reaction (monitored by TLC), the reaction mixture was diluted with DCM and filtered over celite. After solvent removal, the crude was purified by column chromatography (silica gel, hexane/EtOAc = 9:1) to afford 7 as a yellow oil.

In flow synthesis of the target molecule
In flow synthesis of (S)-tert-butyl (1-hydroxy-3-phenylpropan-2-yl)carbamate 2 Two 2.5 mL Hamilton gastight syringes, containing A compound 1 (1 eq.) and Boc2O (1 eq.) in 2 mL of CH2Cl2 (0.25 M), and B aqueous NaOH (2 mL of a 1N solution in water) were connected by a PEEK tee junction to a 500 µL PTFE coil reactor. Both syringes fed the solutions ad 25 µL/min, giving a residence time of 10 minutes. The outcome of the reactor was connected to a Zaiput liquid liquid phase separator, to separate the organic phase from the aqueous phase. The organic phase was dried over sodium sulphate and evaporated under vacuo, to give pure product 2, as evaluated by 1 H NMR, in quantitative yield.
Two 2.5 mL Hamilton gastight syringes, containing A compound 1 (1 eq.) in 2 mL of THF (0.2 M), and B Boc2O (1 eq.) in 2 mL of THF were connected by a PEEK tee junction to a 500 µL PTFE coil reactor.
Both syringes fed the solutions ad 50 µL/min, giving a residence time of 5 minutes. The outcome of the reactor was collected into a vial containing saturated NH4Cl. The organic phase was separated, dried over sodium sulphate and evaporated under vacuo, to give pure product 2, as evaluated by 1 H NMR, in quantitative yield.
Analytical data are in agreement with product obtained using batch procedure. In flow synthesis of (S)-tert-butyl (1-(allyloxy)-3-phenylpropan-2-yl)carbamate 3 S15 Two 2.5 mL Hamilton gastight syringes, containing A compound 2 (1 eq.) in 2 mL of THF (0.1 M), and 4 eq. of allylbromide, and B tBuOK (1.1 eq.) in 2 mL of THF were connected by a PEEK tee junction to a 500 µL PTFE coil reactor. Both syringes fed the solutions ad 25 µL/min, giving a residence time of 10 minutes. The outcome of the reactor was collected into a vial containing saturated NH4Cl. The organic phase was separated, dried over sodium sulphate and evaporated under vacuo, to give product 3 with a 75% conversion, evaluated by 1 H NMR, and confirmed as isolated yield.
Analytical data are in agreement with product obtained in batch procedure. Two 2.5 mL Hamilton gastight syringes, containing A compound 1 (1 eq.) in 2 mL of THF (0.2 M), and B Boc2O (1 eq.) in 2 mL of THF were connected by a PEEK tee junction to a 250 µL PTFE coil reactor.
Both syringes fed the solutions ad 25 µL/min, giving a residence time of 5 minutes. The outcome of the reactor was connected to another tee junction, fed by a 1 mL Hamilton gastight syringe C, containing allylbromide (0.8 mL of 2.4 M solution in THF, 4 equivalents) feeding at 10 µL/min. The outcome of this second tee was connected to another tee junction, fed by a 5 mL Hamilton gastight syringe, D, containing tBuOK (1.6 mL of a 0.33 M solution in THF, 1.1 equivalents) with a flow rate of 20 µL/min. The outcome of this third tee was connected to a 1000 µL PTFE coil reactor, with a total flow rate of 80 µL/min, and a S16 subsequent residence time of 12.5 minutes. The outcome of the reactor was collected into a vial containing saturated NH4Cl. The organic phase was separated, dried over sodium sulphate and evaporated under vacuo, to give product 3 with a 20% conversion, evaluated by 1 H NMR, and confirmed as isolated yield.
Analytical data are in agreement with product obtained in batch procedure.
In flow synthesis of (S)-1-(allyloxy)-3-phenylpropan-2-amine 4 Two 2.5 mL Hamilton gastight syringes, containing A compound 2 (1 eq.) in 2 mL of THF (0.1 M), and 4 eq. of allylbromide, and B tBuOK (1.1 eq.) in 2 mL of THF were connected by a PEEK tee junction to a 500 µL PTFE coil reactor. Both syringes fed the solutions ad 25 µL/min, giving a residence time of 10 minutes. The outcome of the reactor was collected into a vial containing 10% HCl, were it was stirred for further 40 min. Then 1N NaOH was added until basic pH was reached, the organic phase was separated, dried over sodium sulphate and evaporated under vacuo, to give product 4 with a 75% conversion, evaluated by 1 H NMR, and confirmed as isolated yield.
Analytical data are in agreement with product obtained in batch procedure. In flow synthesis of (S,Z)-ethyl 3-((1-(allyloxy)-3-phenylpropan-2-yl)amino)-4,4,4-trifluorobut-2-enoate S17 In flow synthesis of Ethyl 3-(((S)-1-(allyloxy)-3-phenylpropan-2-yl)amino)-4,4,4-trifluorobutanoate 6 S18 Two 2.5 mL Hamilton gastight syringes, containing A compound 10 (2 mL of a 0.8 M solution in CH2Cl2, 1.03 equivalents) and B compound 4 (2 mL of a 0.8 M solution in CH2Cl2, 1 equivalent) were connected by a PEEK tee junction to a 120 µL PTFE coil reactor. Both syringes fed the solutions ad 6 µL/min, giving a residence time of 10 minutes. The outcome of the reactor was connected to another tee junction, fed by a 1 mL Hamilton gastight syringe, C, containing cat. ent-II (0.8 mL of 0.4 M solution in CH2Cl2, 0.2 equivalents) feeding at 2.5 µL/min. The outcome of this second tee was connected to another tee junction, fed by a 5 mL Hamilton gastight syringe, D, containing HSiCl3 (3.3 mL of a 1.9 M solution in CH2Cl2, 4 equivalents) with a flow rate of 10 µL/min. The outcome of this third tee was connected to a 1000 µL PTFE coil reactor, heated at 35°C, with a total flow rate of 24.5 µL/min, and a subsequent residence time of 40 minutes. The outcome of the reactor was collected into a NaOH 4 M solution at 0°C. After the first 2 volumes were discharged, steady state conditions were reached. The conversion of 6, evaluated by 1 H NMR, was reported as an average of three reactors volume, separately collected.
Reactors volumes were reunited and purified by column chromatography to confirm the conversion as isolated yield.
Analytical data are in agreement with product obtained in batch procedure.